Prion protein is a well-characterised and studied protein. Major prion protein to (PrP) also known as CD230 (cluster of differentiation 230) is a protein that in humans is encoded by the PRNP gene (PRioN Protein). The major prion protein is expressed in the brain and several other tissues. The human PRNP gene is located on the short (p) arm of chromosome 20 between the end (terminus) of the arm and position 12, from base pair 4,615,068 to base pair 4,630,233. More than 20 mutations in the PRNP gene have been identified in people with inherited prion diseases, which include Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. Helix 1 is a well characterised alpha-helix within the structure of the PrPc form of the prion protein (cellular/common form of prion protein). Ligands that bind to helix 1 of the PrPc are known, for example antibody ICSM-18 as disclosed in WO2004/050120 and commercially available from D-Gen Limited, UK. Soluble non-fibrillar forms of A[beta] have been implicated in, and shown to correlate with, disease progression in animal models of Alzheimer's disease (AD) and patients with AD9. Low nanomolar concentrations of synthetic A[beta] are known to disrupt synaptic plasticity in vivo and in vitro, but the conformation and size of the A[beta] species responsible remain unclear10-13. It has been reported that the prion protein (PrPc) can act as a cellular receptor for a preparation of synthetic A[beta] referred to as A[beta]-derived diffusible ligands (ADDL) and that PrPc is required for the disruption of synaptic plasticity mediated by ADDL1. Nanomolar affinity of binding has been reported3,4,14 and a single anti-PrP monoclonal antibody with an epitope around residues 95-105 blocked ADDL binding and toxicity1. In further studies, constitutive knockout of PrPc expression reversed several pathological phenotypes in a mouse model of AD2 as did peripheral treatment of the same mouse model with an anti-PrP antibody15. Previous work, as disclosed in WO2008/13034, has concentrated on the ADDL binding site of PrPc, which is found at amino acid residues 95-105 of PrP.
Such a finding is of considerable importance given the extensive investigation of targeting PrPc for prion disease therapeutics16. In particular the abolition of neuronal PrP expression in the adult murine nervous system is without serious consequence17,18 and both small molecule16 and monoclonal antibody therapeutics6 have been extensively studied. Indeed therapeutic molecular interactions with PrPc have been characterised and fully humanised anti-PrP monoclonal antibodies have been produced for clinical studies in human prion disease8,19.
Using available materials, the ADDL binding site of PrP has been targeted in the prior art.
The present invention seeks to overcome problem(s) associated with the prior art.